Acellular and cellular approaches to improve diabetic wound healing
Graphical abstract
Introduction
Diabetes affects more than 422 million people worldwide, including 29.1 million or 9.3% of the US population [1, 2]. A major problem in diabetic individuals is poor or delayed healing of wounds, and consequently chronic non-healing wounds are one of the major complications associated with diabetes. They are estimated to occur in 15% of diabetic patients and responsible for more than 27% of the annual $176 billion diabetic health care cost in the United State [1, 3]. A particularly important and challenging category of diabetic wounds are diabetic foot ulcers (DFUs) [4]. Annual incidence rates of DFUs are estimated to be 6.3% in diabetic individuals globally [5]. In the U.S., DFUs cause 20% of all diabetic hospital admissions and account for more than 60% of non-traumatic lower limb amputations each year, with only a 40% 5-year survival rate after amputation [1, 6]. With a recent projection [7] that up to 1 in 3 US adults could have diabetes by 2050, the impact and costs associated with chronic diabetic wounds are expected to rise very sharply, motivating the pursuit of novel therapeutics.
In healthy individuals, a normal wound healing process occurs that consists of three overlapping, yet distinct phases of inflammation, proliferation, and remodeling, with different cell types, growth factors, and cytokines playing important roles at each of the phases to orchestrate smooth progression of the healing cascade. During the inflammatory phase, extravasation of blood components causes the formation of a fibrin clot, which acts as a temporary provisional scaffold for infiltrating cells. Neutrophils are the first cells to arrive at the site of injury to clean and destroy foreign materials, damaged cells, and bacteria. Monocytes are then attracted to the wound site in response to chemoattractants, such as TGF-β and MCP-1, and differentiate into macrophages that initiate the proliferative phase of wound healing, which is characterized by migration and proliferation of different cell types, including endothelial cells, fibroblasts, and keratinocytes that are responsible for angiogenesis, granulation tissue formation, extracellular matrix deposition, wound contraction, and re-epithelization [8, 9]. During the remodeling phase of wound healing, the number of neovessels decline and most of the cells involved in the proliferative phase either leave from the wound or undergo apoptosis, leaving a mature, mostly avascular environment with few cells [10]. In addition, type III collagen that was expressed earlier in the granulation tissue is gradually replaced by stronger type I collagen, which increases the tensile strength of the scar tissue to up to 80% of uninjured skin [11]. For interested readers, further details describing cellular and molecular mechanisms during wound healing have been summarized elsewhere [8, [12], [13], [14]].
In diabetic wounds, healing is stalled in the inflammatory phase that is characterized by elevated levels of proinflammatory cytokines, proteases, and reactive oxygen species (ROS), as well as cellular dysfunctions [15, 16]. Due to impaired immune responses, such as defective phagocytic and chemotactic activities of granulocytes [17], diabetic wounds are more prone to infection, which results in excessive recruitment of inflammatory cells that produce various ROS and damage structural elements of the extracellular matrix (ECM) [18]. Coupled with elevated levels of proinflammatory cytokines, ROS induces expression of serine proteases and matrix metalloproteinases (MMPs), leading to degradation of the ECM and growth factors, as well as the proteinase inhibitors, which further impairs the wound from mounting an adequate inflammatory response. In addition, ischemia secondary to vascular defects creates chronic wound hypoxia due to lack of proper perfusion, resulting in the release of more ROS [19] that, in turn, increases the proteins’ susceptibility to proteolytic degradation [20]. These added proteolytic insults induce severe ECM degradation, which prevents normal matrix-cell interactions necessary for wound repair. As a result, the wound enters into a vicious cycle of defined by its prolonged inflammatory phase and characterized by a dysregulated molecular and cellular wound microenvironment that is not conducive to normal healing responses (Fig. 1). Therefore, correcting wound microenvironment dysfunction by sequestering wound proteases and/or modifying the ECM to more proteolytically-stable and cell-friendly conditions for migration and proliferation could be a viable treatment strategy to tilt the wounds from chronic inflammation towards the normal healing cascade.
In addition to the unbalanced, inadequate local wound microenvironment, dermal cells from chronic diabetic wounds show a decreased response to environmental stimuli, partly due to a lower density of growth factor receptors [18]. Hyperglycemia-induced molecular changes, including formation and accumulation of advanced glycation end products (AGEs), adversely and irreversibly modify both intracellular and extracellular environments [21]. These changes are known to impair both endothelial cell [22] and fibroblast [23] functions, which results in decreased neovascularization and reduced granulation tissue formation and ECM deposition. In addition, AGEs could elicit production of ROS by binding to its receptor (RAGE) expressed in various skin cells including keratinocytes, fibroblasts, dendrocytes, and to a lesser extent in endothelial cells and mononuclear cells [24], and induce the activation of NF-κB [21], which results in pathological gene expression [25] and further impedes the normal activity of these cells during wound healing. Hyperglycemia-induced epigenetic changes in the cells are another source of delay in wound healing responses in diabetic patients. It has been shown that macrophages [26], vascular smooth muscle cells [27], and endothelial cells [28, 29] isolated from diabetic rodents or cultured in high glucose conditions exhibit a persistent proinflammatory phenotype via histone modifications. Therefore, cell-based therapies aimed to correct hyperglycemia-induced changes in cells could present a novel treatment option for diabetic wounds.
Current treatment options for diabetic wounds include pressure offloading, sharp tissue debridement, infection management using antibiotics, and revascularization surgery to restore blood flow [2]. These treatment strategies are aimed at wound closure rather than addressing the underlying pathophysiology of the wounds, which results in variability of healing effects, extended healing time, and recurrence of wound, leading to treatment failure and amputation [2, [30], [31], [32], [33], [34]]. Recent breakthroughs in both the scientific understanding of the wound healing process and biotechnology have enabled the introduction of new biological products [30, 31] that have gained FDA approval. Regranex® is sodium carboxymethyl cellulose gel containing becaplermin, a recombinant human platelet-derived growth factor (rh-PDGF-BB) which has shown its efficacy in several studies [[35], [36], [37], [38], [39]]. Cell-based bioengineered skin constructs such as Apligraf® and Dermagraft® have also been shown to significantly reduce healing time for chronic wounds [40, 41]. However, the FDA added a black box warning to the label of Regranex, due to the possible risk of cancer associated with the use of three or more becaplermin gel tubes [42], and the cell-based bioengineered skin constructs have much shorter half-life with stricter storage conditions and higher cost to payer without conclusive superiority in shortening the healing time when compared with the acellular skin construct counterparts [43]. Therefore, there is clearly a great need for improvements in treatment strategies for diabetic wounds. Due to multifactorial origins of wound etiology, there is no single universal mechanism that could explain the persistence of wounds in diabetic patients, and therefore a combination of different therapeutic approaches aimed for correcting multiple deficits simultaneously would help lead to a successful outcome for diabetic wound healing. In the following sections, various reparative and regenerative efforts focused on accelerating diabetic wound healing will be discussed. As a first part of this review, therapeutic approaches targeted on modifying the local wound microenvironment (ECM) using tissue engineering scaffolds in the presence or absence of drugs will be presented. Then, approaches focused on correcting cellular-deficiency using cell-based therapies will be discussed.
Section snippets
Drug delivery for diabetic wound healing
Wound bed preparation is a widely accepted concept to remove underlying molecular and cellular barriers to facilitate healing [44]. Thorough wound bed preparation can sometimes be sufficient to induce normal healing responses in complicated wounds. More often than not, however, additional therapies are necessary to restore normal healing responses in chronic diabetic wounds. Systemic drug delivery, via either an oral or intravenous approach, has been a typical route of administration. However,
Tissue-engineered scaffolds: vehicles for overcoming obstacles
Wound healing involves dynamic interactions between cells, the ECM, and growth factors. The ECM is a non-cellular component in all tissues and organs. It is a major constituent of the skin layer and is comprised of structural proteins, such as collagens, fibronectin, laminin, proteoglycans, glycosaminoglycans, and other non-structural matricellular proteins. In addition to providing a structural support for cells, the ECM acts as a reservoir of growth factors that are rapidly mobilized to
Cells as therapeutics for diabetic wound healing
The complexity of the multi-step process of wound healing and skin regeneration has limited the success of both single drug and gene therapies. Even when these therapies have been designed to specifically home to the wound site, the necessity and precision with which these drugs must recapitulate their physiological spatial and temporal presentation is a barrier, which has not yet been overcome. Further, the traditionally defined trajectory of wound healing is significantly altered or halted in
Conclusion
Despite recent advances, treating diabetic wounds to heal in a timely manner still remains a challenge due to their multifactorial etiology. Therefore, integrating multiple therapeutic approaches is necessary to facilitate the healing process. As such, there have been numerous studies testing the feasibility of using different materials for the delivery of various bioactive agents, including growth factors, siRNAs, microRNAs, small molecules, or cells. However, a majority of these studies have
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